Project Summary/abstract Distal symmetric polyneuropathy (DSP) affects upwards of 15% of Americans over the age of 40. This highly prevalent condition impairs patient's quality of life, causes pain, and results in falls. Patients with DSP caused by diabetes are at particular risk for ulcerations and lower extremity amputations. Despite the large population affected by this disease and the significant morbidity that results, no disease modifying therapies exist to prevent nerve injury. Neuropathic pain medications can reduce the pain from DSP, but do not prevent nerve damage. Enhanced glucose control has been proven to prevent DSP in patients with type 1 diabetes, but has only a small effect on patients with type 2 diabetes. As a result, a critical need exists to develop disease modify therapies for patients with and at risk for DSP. We propose two potential disease modifying therapies, namely exercise and/or weight loss. To determine the impact of exercise on DSP outcomes, we plan to randomize patients to high intensity interval training (HIIT) or routine exercise counseling. We chose HIIT as our exercise regimen because of data supporting increased compliance in patients with obesity and diabetes. This innovative intervention also has emerging data to support improved metabolic outcomes in patients with diabetes. We hypothesize that exercise will have the largest effect on DSP outcomes because of three previous uncontrolled studies documenting substantial improvement in intraepidermal nerve fiber density and cutaneous regenerative capacity in those receiving an exercise regimen with little to no weight loss. By comparison, in an uncontrolled study, we found stable IENFD after two years of significant medical weight loss. While the natural history of IENFD is to decrease in those with diabetes and pre-diabetes, improvement in IENFD was not seen despite robust weight loss. We propose to determine the effect of weight loss on DSP outcomes by studying a bariatric surgery population where 55% of the patients have surgery once they are approved by the surgery review committee. We will stratify HIIT randomization 1:1 to those that do and those that do not undergo surgery. This non-randomized design will allow comparison of the effect of surgery to HIIT without the need for an expensive, randomized surgical intervention trial. Surgical weight loss may have a more robust effect on DSP outcomes than medical weight loss because of the magnitude and sustainability of weight loss. We will also be able to investigate the effect of combining surgical weight loss and HIIT. The proposed aims have the potential to identify promising exercise and/or weight loss interventions for DSP. This phase 2 study may lead to a definitive phase 3 trial, which would possibly result in the first disease modifying therapy for DSP. Given the high prevalence and substantial morbidity associated with DSP, such an intervention is desperately needed.